This invention relates to phthalimido derivatives and a process for preparing these compounds.
This invention relates to phthalimido derivatives of the formula 
wherein
X is xe2x80x94Nxe2x95x90 or xe2x80x94CHxe2x95x90;
R1 is xe2x80x94COxe2x80x94NR5R6;
xe2x80x94CHR7xe2x80x94(CH2)nxe2x80x94COxe2x80x94NR5R6;
xe2x80x94(CH2)nxe2x80x94NR5R6;
xe2x80x94(CH2)nxe2x80x94COOR8;
xe2x80x94(CH2)nxe2x80x94CN;
xe2x80x94CHR7xe2x80x94(CH2)nxe2x80x94CF3;
xe2x80x94(CH2)nxe2x80x94NHxe2x80x94COR9;
xe2x80x94(CH2)nxe2x80x94NHxe2x80x94COOR8;
xe2x80x94(CH2)n-piperidinyl, xe2x80x94(CH2)n-morpholinyl, xe2x80x94(CH2)n-tetrahydrofuranyl; xe2x80x94(CH2)n-thiophenyl or xe2x80x94(CH2)n-isoxazolyl, wherein the heterocyclic ring may be substituted by C1-C6-alkyl;
xe2x80x94(CH2)n-phenyl, wherein the phenyl ring may be substituted by halogen or halogen-(C1-C6)-alkyl;
xe2x80x94(CH2)pxe2x80x94OR8;
xe2x80x94(CH2)pxe2x80x94SR8;
xe2x80x94(CH2)pxe2x80x94SOxe2x80x94R9; or
xe2x80x94(CH2)nxe2x80x94CSxe2x80x94NR5R6;
R2 is hydrogen;
C1-C6-alkyl;
xe2x80x94(CH2)pxe2x80x94OR10;
xe2x80x94(CH2)pxe2x80x94SR10; or benzyl;
R3 is hydrogen or C1-C6-alkyl;
R4 is halogen, halogen-(C1-C6)-alkyl, cyano, C1-C6-alkoxy or halogen-(C1-C6)-alkoxy;
R5 and R6 are independently from each other hydrogen or C1-C6-alkyl;
R7 is hydrogen, hydroxy or C1-C6-alkoxy;
R8 is hydrogen or C1-C6-alkyl;
R9 is C1-C6-alkyl;
R10 is hydrogen or C1-C6-alkyl;
m is 1, 2 or 3;
n is 0, 1 or 2; and
p is 1 or 2;
or a pharmaceutically acceptable salt thereof.
It has now been found that the compounds of formula I are selective monoamine oxidase B inhibitors.
Monoamine oxidase (MAO, EC 1.4.3.4) is a flavin-containing enzyme responsible for the oxidative deamination of endogenous monoamine neurotransmitters such as dopamine, serotonin, adrenaline, or noradrenaline, and trace amines, e.g. phenylethylamine, as well as a number of amine xenobiotics. The enzyme exists in two forms, MAO-A and MAO-B, encoded by different genes (A. W. Bach et al., Proc. Natl. Acad. Sci. USA 1988, 85, 4934-4938) and differing in tissue distribution, structure and substrate specificity. MAO-A has higher affinity for serotonin, octopamine, adrenaline, and noradrenaline; whereas the natural substrates for MAO-B are phenylethylamine and tyramine. Dopamine is thought to be oxidised by both isoforms. MAO-B is widely distributed in several organs including brain (A. M. Cesura and A. Pletscher, Prog. Drug Research 1992, 38, 171-297). Brain MAO-B activity appears to increase with age. This increase has been attributed to the gliosis associated with aging (C. J. Fowler et al., J. Neural. Transm. 1980, 49, 1-20).
Additionally, MAO-B activity is significantly higher in the brains of patients with Alzheimer""s disease (P. Dostert et al., Biochem. Pharmacol. 1989, 38, 555-561) and it has been found to be highly expressed in astrocytes around senile plaques (Saura et al., Neuroscience 1994, 70, 755-774). In this context, since oxidative deamination of primary monoamines by MAO produces NH3, aldehydes and H2O2, agents with established or potential toxicity, it is suggested that there is a rationale for the use of selective MAO-B inhibitors for the treatment of dementia and Parkinson""s disease. Inhibition of MAO-B causes a reduction in the enzymatic inactivation of dopamine and thus prolongation of the availability of the neurotransmitter in dopaminergic neurons. The degeneration processes associated with age and Alzheimer""s and Parkinson""s diseases may also be attributed to oxidative stress due to increased MAO activity and consequent increased formation of H2O2 by MAO-B. Therefore, MAO-B inhibitors may act by both reducing the formation of oxygen radicals and elevating the levels of monoamines in the brain.
Given the implication of MAO-B in the neurological disorders mentioned above, there is considerable interest to obtain potent and selective inhibitors that would permit control over this enzymatic activity. The pharmacology of some known MAO-B inhibitors is for example discussed by D. Bentuxc3xa9-Ferrer et al. in CNS Drugs 1996, 6, 217-236. Whereas a major limitation of irreversible and non-selective MAO inhibitor activity is the need to observe dietary precautions due to the risk of inducing a hypertensive crisis when dietary tyramine is ingested, as well as the potential for interactions with other medications (D. M. Gardner et al., J. Clin. Psychiatry 1996, 57, 99-104), these adverse events are of less concern with reversible and selective MAO inhibitors, in particular of MAO-B. Thus, there is a need for MAO-B inhibitors with a high selectivity and without the adverse side-effects typical of irreversible MAO inhibitors with low selectivity for the enzyme.
This invention is directed to phthalimido derivatives of the formula 
wherein
X is xe2x80x94Nxe2x95x90 or xe2x80x94CHxe2x95x90;
R1 is xe2x80x94COxe2x80x94NR5R6;
xe2x80x94CHR7xe2x80x94(CH2)nxe2x80x94COxe2x80x94NR5R6;
xe2x80x94(CH2)nxe2x80x94NR5R6;
xe2x80x94(CH2)nxe2x80x94COOR8;
xe2x80x94(CH2)nxe2x80x94CN;
xe2x80x94CHR7xe2x80x94(CH2)nxe2x80x94CF3;
xe2x80x94(CH2)nxe2x80x94NHxe2x80x94COR9;
xe2x80x94(CH2)nxe2x80x94NHxe2x80x94COOR8;
xe2x80x94(CH2)nxe2x80x94piperidinyl, xe2x80x94(CH2)n-morpholinyl, xe2x80x94(CH2)n-tetrahydrofuranyl; xe2x80x94(CH2)n-thiophenyl or xe2x80x94(CH2)n-isoxazolyl, wherein the heterocyclic ring may be substituted by C1-C6-alkyl;
xe2x80x94(CH2)n-phenyl, wherein the phenyl ring may be substituted by halogen or halogen-(C1-C6)-alkyl;
xe2x80x94(CH2)pxe2x80x94OR8;
xe2x80x94(CH2)pxe2x80x94SR8;
xe2x80x94(CH2)pxe2x80x94SOxe2x80x94R9; or
xe2x80x94(CH2)nxe2x80x94CSxe2x80x94NR5R6;
R2 is hydrogen;
C1-C6-alkyl;
xe2x80x94(CH2)pxe2x80x94OR10;
xe2x80x94(CH2)pxe2x80x94SR10; or benzyl;
R3 is hydrogen or C1-C6-alkyl;
R4 is halogen, halogen-(C1-C6)-alkyl, cyano, C1-C6-alkoxy or halogen-(C1-C6)-alkoxy;
R5 and R6 are independently from each other hydrogen or C1-C6-alkyl;
R7 is hydrogen, hydroxy or C1-C6-alkoxy;
R8 is hydrogen or C1-C6-alkyl;
R9 is C1-C6-alkyl;
R10 is hydrogen or C1-C6-alkyl;
m is 1, 2 or 3;
n is 0, 1 or 2; and
p is 1 or 2;
or a pharmaceutically acceptable salt thereof.
The compounds of this invention have the advantageous properties mentioned above. It has been found that the compounds of formula I of the present invention and their pharmaceutically acceptable salts show the potential to be highly selective MAO-B inhibitors. Subjects of the present invention are further pharmaceutical compositions based on a compound of formula I in accordance with the invention, a method of treating a disease mediated by monoamine oxidase B inhibitors by administering a therapeutically effective amount of at least one of these compounds, and a process for preparing these compounds.
The following definitions of general terms used in the present patent application apply irrespective of whether the terms in question appear alone or in combination. It must be noted that, as used in the specification and the appended claims, the singular forms xe2x80x9caxe2x80x9d, xe2x80x9can,xe2x80x9d and xe2x80x9cthexe2x80x9d include plural forms unless the context clearly dictates otherwise.
The term xe2x80x9cC1-C6-alkylxe2x80x9d (xe2x80x9clower alkylxe2x80x9d) used in the present application denotes straight-chain or branched saturated hydrocarbon residues with 1 to 6 carbon atoms, preferably with 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, and the like.
The term xe2x80x9chalogenxe2x80x9d denotes fluorine, chlorine, bromine and iodine.
xe2x80x9cHalogen-(C1-C6)-alkylxe2x80x9d or xe2x80x9chalogen-(C1-C6)-alkoxyxe2x80x9d means the lower alkyl residue or lower alkoxy residue, respectively, as defined herein substituted in any position with one or more halogen atoms as defined herein. Examples of halogenalkyl residues include, but are not limited to, 1,2-difluoropropyl, 1,2-dichloropropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and 1,1,1-trifluoropropyl, and the like.xe2x80x9cHalogenalkoxyxe2x80x9d includes trifluoromethyloxy.
xe2x80x9cC1-C6-Alkoxyxe2x80x9d means the residue xe2x80x94Oxe2x80x94R, wherein R is a lower alkyl residue as defined herein. Examples of alkoxy radicals include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.
xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d of a compound means salts that are pharmaceutically acceptable, which are generally safe, non-toxic, and neither biologically nor otherwise undesirable, and that possess the desired pharmacological activity of the parent compound. These salts are derived from an inorganic or organic acid or base.
Such salts include:
(91) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluene-sulfonic acid, trimethylacetic acid, 2,2,2-trifluoroacetic acid, and the like; or
(2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) of the same acid addition salt.
Among compounds of the present invention certain compounds of formula I, or pharmaceutically acceptable salts thereof, are preferred.
Preferred compounds of formula I are those, in which X is xe2x80x94CHxe2x95x90.
Especially preferred are compounds of formula I, in which R1 is xe2x80x94COxe2x80x94NR5R6 or xe2x80x94CHR7xe2x80x94(CH2)nxe2x80x94COxe2x80x94NR5R6, and wherein R5 and R6 are independently from each other hydrogen or C1-C6-alkyl, R7 is hydrogen, hydroxy or C1-C6-alkoxy and n is 0, 1 or 2.
Examples of such compounds are the following:
2-[5-(4-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-acetamide,
(S)-2-[5-(4-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-propionamide,
(S)-2-[5-(4-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-3-hydroxy-propionamide,
(R)-2-[5-(4-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-propionamide,
2-[5-(3-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-propionamide,
(2-[5-(3-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-acetamide, and
2-[5-(3-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-3-hydroxy-propionamide.
Also preferred are compounds of formula I, in which R1 is xe2x80x94(CH2)nxe2x80x94NR5R6, xe2x80x94(CH2)nxe2x80x94NHxe2x80x94COR9 or xe2x80x94(CH2)nxe2x80x94piperidinyl, and wherein R5 and R6 are independently from each other hydrogen or C1-C6-alkyl, R9 is C1-C6-alkyl and n is 0, 1, or 2.
The following compounds are examples thereof:
N-{2-[5-(4-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-ethyl}-acetamide,
2-(2-amino-ethyl)-5-(4-fluoro-benzyloxy)-isoindole-1,3-dione, and
5-(4-fluoro-benzyloxy)-2-piperidin-4-yl-isoindole-1,3-dione.
Further preferred compounds of formula I are those, in which R1 is xe2x80x94(CH2)pxe2x80x94OR8 or xe2x80x94CHR7xe2x80x94(CH2)nxe2x80x94CF3, and wherein R7 is hydrogen, hydroxy or C1-C6-alkoxy, R8 is hydrogen or C1-C6-alkyl and p is 1 or 2. Examples of such compounds are the following:
5-(4-fluoro-benzyloxy)-2-(2-hydroxy-ethyl)-isoindole-1,3-dione,
5-(4-fluoro-benzyloxy)-2-(2-methoxy-ethyl)-isoindole-1,3-dione,
5-(3-fluoro-benzyloxy)-2-(2-methoxy-ethyl)-isoindole-1,3-dione,
(S)-5-(4-fluoro-benzyloxy)-2-(2-methoxy-1-methyl-ethyl)-isoindole-1,3-dione,
(S)-5-(3-fluoro-benzyloxy)-2-(2-methoxy-1-methyl-ethyl)-isoindole-1,3-dione,
(S)-5-(2-fluoro-benzyloxy)-2-(2-methoxy-1-methyl-ethyl)-isoindole-1,3-dione,
(S)-2-(2-methoxy-1-methyl-ethyl)-5-(4-trifluoromethyl-benzyloxy)-isoindole-1,3-dione,
(S)-5-(4-bromo-benzyloxy)-2-(2-methoxy-1-methyl-ethyl)-isoindole-1,3-dione,
(S)-5-(3,4-difluoro-benzyloxy)-2-(2-methoxy-1-methyl-ethyl)-isoindole-1,3-dione,
5-(3-fluoro-benzyloxy)-2-(2-hydroxy-ethyl)-isoindole-1,3-dione,
5-(4-fluoro-benzyloxy)-2-(3,3,3-trifluoro-2-hydroxy-propyl)-isoindole-1,3-dione, and
5-(3,5-bis-trifluoromethyl-benzyloxy)-2-(2-methoxy-1-methyl-ethyl)-isoindole-1,3-dione.
Preferred compounds of formula I are further those, in which R1 is xe2x80x94(CH2)pxe2x80x94SR8; xe2x80x94(CH2)pxe2x80x94SOxe2x80x94R9; or xe2x80x94(CH2)nxe2x80x94CSxe2x80x94NR5R6, and wherein R5 and R6 are independently from each other hydrogen or C1-C6-alkyl, R8 is hydrogen or C1-C6-alkyl, R9 is C1-C6-alkyl and n is 0, 1, or 2. Examples of such compounds are the following:
2-(2-ethylsulfanyl-ethyl)-5-(4-fluoro-benzyloxy)-isoindole-1,3-dione,
(S)-2-[5-(4-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-thiopropionamide, and
2-(2-ethylsulfanyl-ethyl)-5-(3-fluoro-benzyloxy)-isoindole-1,3-dione.
Also preferred are compounds of formula I, in which R1 is xe2x80x94(CH2)nxe2x80x94CN and n is 0, 1 or 2. The following compounds are examples thereof:
5-(4-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-acetonitrile, and
[5-(3-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-acetonitrile.
Preferred are also compounds of formula I, in which R4 signifies halogen. Especially preferred are compounds of formula I, in which R4 is fluoro and m is 1.
The compounds of formula I and their pharmaceutically acceptable salts can be manufactured by reacting a compound of formula 
with a compound of formula 
to obtain a compound of formula 
and, if desired, converting a compound of formula I into a pharmaceutically acceptable salt.
Alternatively, the compounds of formula I and their pharmaceutically acceptable salts can be manufactured by reacting a compound of formula 
with a compound of formula 
to obtain a compound of formula 
and, if desired, converting a compound of formula I into a pharmaceutically acceptable salt.
In accordance with the present invention, compounds of formula I can be prepared following scheme 1: A compound of formula VI is heated in the presence of ammonium carbonate. The obtained compound VII is then treated with benzylic bromides in the presence of potassium carbonate to afford compounds of type IV which are then dissolved in THF and treated with sodium hydride and an electrophile of formula V to give compounds of formula I. 
Alternatively, in accordance with the present invention, compounds of formula I can be prepared following scheme 2: A compound of formula VI is heated in the presence of benzylic bromides and potassium carbonate to afford VIII which are then saponified with bases such as LiOH to give IX. Treatment of IX with an activating agent such as carbonyldiimidazole in an appropriate solvent such as DMF or DMA or NMP, followed by heating (conventional or microwave) in the presence of amines III affords compounds of formula I. 
Alternatively, in accordance with the present invention, compounds of formula I can be prepared following scheme 3: A compound of formula VI is heated in the presence of an amine III with an activating agent such as carbonyldiimidazole in an appropriate solvent such as dimethylformamide (DMF) or dimethylacetamide (DMA) or N-methyl-pyrrolidone (NMP), followed by heating (conventional or microwave) to afford compounds of formula X which are in turn reacted with benzyl bromides in the presence of potassium carbonate to give compounds of formula I. 
Alternatively, in accordance with the present invention, compounds of formula XVI can be prepared following scheme 4: A compound of formula XI is oxidized to XII and chlorinated to give XIII via successive treatment with m-chloroperoxybenzoic acid (m-CPBA) followed by phosphorus oxychloride. Subsequent reaction with sodium salts of benzyl alcohols affords XIV which after saponification to compounds of type XV are treated with an activating agent such as carbonyldiimidazole in an appropriate solvent such as DMF or DMA or NMP, followed by heating (conventional or microwave) in the presence of amines III affords compounds of formula XVI. 
Pharmaceutically acceptable salts of compounds of formula I can be manufactured readily according to methods known in the art and taking into consideration the nature of the compound to be converted into a salt. Inorganic or organic acids such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulphonic acid and the like are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I. Compounds which contain the alkali metals or alkaline earth metals, for example sodium, potassium, calcium, magnesium or the like, basic amines or basic amino acids are suitable for the formation of pharmaceutically acceptable salts of acidic compounds.
The compounds of formula I and their pharmaceutically acceptable salts are, as already mentioned above, monoamine oxidase B inhibitors and can be used for the treatment or prevention of diseases in which MAO-B inhibitors might be beneficial. These include acute and chronic neurological disorders, cognitive disorders and memory deficits. Treatable neurological disorders are for instance traumatic or chronic degenerative processes of the nervous system, such as Alzheimer""s disease, other types of dementia, minimal cognitive impairment or Parkinson""s disease. Other indications include psychiatric diseases such as depression, anxiety, panic attack, social phobia, schizophrenia, eating and metabolic disorders such as obesity as well as the prevention and treatment of withdrawal syndromes induced by abuse of alcohol, nicotine and other addictive drugs. Other treatable indications may be reward deficiency syndrome (G. M. Sullivan, International patent application No. WO 01/34172 A2), peripheral neuropathy caused by cancer chemotherapy (G. Bobotas, International Patent Application No. WO 97/33572 A1), or the treatment of multiple sclerosis (R. Y. Harris, International patent application No. WO 96/40095 A1) and other neuroinflammatory diseases.
The compounds of formula I and their pharmaceutically acceptable salts are especially useful for the treatment and prevention of Alzheimer""s disease and senile dementia.
The pharmacological activity of the compounds was tested using the following method:
The cDNA""s encoding human MAO-A and MAO-B were transiently transfected into EBNA cells using the procedure described by E.-J. Schlaeger and K. Christensen (Transient Gene Expression in Mammalian Cells Grown in Serum-free Suspension Culture; Cytotechnology, 15: 1-13, 1998). After transfection, cells were homogenized by means of a Polytron homogenizer in 20 mM Tris HCl buffer, pH 8.0, containing 0.5 mM EGTA and 0.5 mM phenylmethanesulfonyl fluoride. Cell membranes were obtained by centrifugation at 45,000 x g and, after two rinsing step with 20 mM Tris HCl buffer, pH 8.0, containing 0.5 mM EGTA, membranes were eventually re-suspended in the above buffer and aliquots stored at xe2x88x9280xc2x0 C. until use.
MAO-A and MAO-B enzymatic activity was assayed in 96-well-plates using a spectrophotometric assay adapted from the method described by M. Zhou and N. Panchuk-Voloshina (A One-Step Fluorometric Method for the Continuous Measurement of Monoamine Oxidase Activity, Analytical Biochemistry, 253: 169-174, 1997). Briefly, membrane aliquots were incubated in 0.1 M potassium phosphate buffer, pH 7.4, for 30 min at 37xc2x0 C. with or without various concentrations of the compounds. After this period, the enzymatic reaction was started by the addition of the MAO substrate tyramine together with 1 U/ml horse-radish peroxidase (Roche Biochemicals) and 80 xcexcM N-acetyl-3,7,-dihydroxyphenoxazine (Amplex Red, Molecular Probes). The samples were further incubated for 30 min at 37xc2x0 C. in a final volume of 200 xcexcl and absorbance was then determined at a wavelength of 570 nm using a SpectraMax plate reader (Molecular Devices). Background (non-specific) absorbance was determined in the presence of 10 xcexcM clorgyline for MAO-A or 10 xcexcM L-deprenyl for MAO-B.
IC50 values were determined from inhibition curves obtained using nine inhibitor concentrations in duplicate, by fitting data to a four parameter logistic equation using a computer program.
The compounds of the present invention are specific MAO-B inhibitors. The IC50 values of compounds of formula I as measured in the assay described above are in the range of 10 xcexcM or less, preferably of 1 xcexcM or less, more preferably 0.03 xcexcM or less, and most preferably 0.1 xcexcM or less.
In the table below are described some specific IC50 values of preferred compounds.
The compounds of formula I and pharmaceutically acceptable salts thereof can be used in pharmaceutical compositions. The pharmaceutical compositions can be administered orally, e.g. in the form of tablets, coated tablets, dragxc3xa9es, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragxc3xa9es  and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula I, but as a rule are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
In addition, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.
As mentioned earlier, this invention provides for pharmaceutical compositions containing a compound of formula I or pharmaceutically acceptable salts thereof and a therapeutically inert excipient, as is a process for the production of such pharmaceutical compositions, which comprises bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day being preferred for all of the indications described. The daily dosage for an adult human being weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably between 7 and 700 mg per day.